A- Lycorane

One of these products (49) was used as a key intermediate for the synthesis of the Amaryllidaceae alkaloids a- and /-lycorane (Scheme 12)53. A copper-catalyzed Grignard reaction with 49 afforded 50 via a selective y-anti displacement of the chloride. Hydrogenation followed by Bischler-Napieralski cyclization gave 51. Interestingly, reversal of the latter two steps gave the isomer 52 where an epimerization at the benzylic carbon had occurred in the cyclization step (>99% selectivity). Subsequent reduction of the amide in each case afforded the target molecules a- and y-lycorane, respectively. The purity of the final product was very high with respect to the opposite stereoisomer. Thus <0.2% of /-lycorane was present in a-lycorane and vice versa. 

Lycorine. Boeckman s particularly elegant synthesis [65] (Scheme 41) of the most abundant Amaryllidaceae alkaloid, (-)-lycorine (245) [66], known since 1877 [67], involved an intramolecular Diels-Alder reaction of an appropriately functionalised azatrienic system. This approach (A + D - AD - ADCB) somewhat reminiscent of the one used by Stork for ( )-7-oxo-a-lycorane [68], possessed the virtue of establishing the correct stereochemistry of four... 

An alternative synthesis of ( )-a- and ( )--y-lycoranes (57 and 93) commenced with the 2-oxocyclohexyl acetic acid derivative 114 obtained by the alkylation of the enamine derived from 113 (Scheme 10) (116). Refluxing the oxime of 114 with zinc dust in glacial acetic acid afforded a mixture of the lactams 115, 116, and 117 in an approximate ratio of 4 6 3. The structure of 115 was verified by catalytic hydrogenation to give the lactam 118, which had previously been converted to ( )-a-lycorane (57). When the lactam 116 was subjected to sequential catalytic hydrogenation, hydride reduction, and Pictet-Spengler cyclization, ( )-y-lycorane (93) was obtained. A more efficient route to ( )-a-lycorane (57) involved refluxing the ketone 114 first with benzylamine in xylene and then with 87% formic acid to furnish the unsaturated lactam 119. 

An intramolecular [3 + 2] dipolar cycloaddition reaction has also been exploited in the design of a concise, stereospecific synthesis of ( )-a-lycorane (57) (119). Thus, cyclization of the azomethine ylide 145, which was produced in situ by the reaction of 144 with IV-benzylglycine, in refluxing toluene furnished the cw-hydroindole 146 as the exclusive product (Scheme 14). The transformation of 146 to racemic a-lycorane (57) was then achieved by N-debenzylation via catalytic, transfer hydrogenation and subsequent Pictet-Spengler cyclization. 

An alternative is to put the alkene in another place 84 and discover a different pair of diene 86 and dienophile 85. Again the -isomers will be easier to make and this time we get the right stereochemistry 88 for a-lycorane 71. This strategy was followed in an early synthesis by Hill.9 Another synthesis using the Diels-Alder reaction is by Irie.10 More details appear in the workbook. 

Synthesis This is the method used in the synthesis of TM271 as an intermediate for a-lycorane (j. Amer. Chem. Soc.. 1962,, 4951). 

The Ru-catalyzed asymmetric hydrogenation of racemic a-substituted cyclic ketones was applied to the synthesis of various chiral natural products and analogs, such as (-)-galanthamine [80], (-)-ALTHC [81], CP 55,940 [82], and (-)-a-lycorane [83]. 

The syntheses of (-l-)-a -lycorane (92) and (+)-trianthine (97) using the retro-Cope elimination step 122), and of (-l-)- y-lycorane (100) using the palladium-mediated reaction 123), have been reported. 

When optically active 2-(cyclohex-2-enyl)ethylhydroxylamine (90) [derived from methyl 3-(3,4-methylenedioxy)phenylcyclohex-2-enyl acetate] was heated at 140°C, the A-hydroxyhexahydroindoline 91 was obtained in 83% yield. Reductive cyclization of 91 then gave (-l-)-a -lycorane (92) (Scheme 6). 

Diene condensation of 3,4-methylenedioxy-j8-nitrostyrene and methyl hexa-3,5-dienoate afforded the adduct (XXI). Catalytic reduction of the olefinic and nitro groups occurred with spontaneous formation of the lactam (XXII). Lithium aluminum hydride reduction of XXII followed by Pictet-Spengler cyclization afforded ( + )-a-lycorane, identical in its IR-spectrum with (— )-a-lycorane. 

Alternative syntheses of a-lycorane (23) and y-lycorane (25) depend on the preparation of unsaturated lactams (20) and (21) whereby ring c is derived from an aryl-cyclohexanone (17) (Scheme 2). Reduction of the oxime of the 2-... 

Acetaldehyde also engaged in other conjugate additions with poly-conjugated substrates, such as nitrodienynes and nitroenynes. Interestingly, only 1,4-additions were observed and no 1,6- or 1,8-addition occurred. The utility of the products was demonstrated by the enantioselective total synthesis of (- -)-a-lycorane (Scheme 8.2). ... 

Synthetic Applications The intramolecular 1,4-chloroamination of 108 was apphed to the synthesis of amaryllidaceae alkaloids a- and ylycotane (Scheme 11.40) [129]. The hexahydroindole 109 obtained was transformed to the target alkaloid a-lycorane by a copper-catalyzed reaction with 3,4-(methylene-dioxy)phenyhnagnesium bromide, followed by hydrogenation, the Bischler-Napieralski cyclization, and LiAlH reduction. When the Bischler-Napieralski cyclization was carried out before the hydrogenation, ylycorane was the sole product. 

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